For the achievement of certain desired effects it is advantageous to release one or several substances in the large intestine of a mammal. The desired effects can be, for example, the specific administration of one or several substances which have a particular therapeutic efficacy if they are released in the large intestine, for example, by the fact that they have an effect there directed on the large intestine mucosa can have an effect on bacteria of the large intestine flora or unfold a better systemic efficacy by special absorption ability of the large intestine mucosa or by avoidance of digestion juices present in the small intestine. Further desired effects of the release of one or several substances in the large intestine of a mammal are known to the person skilled in the art.
One knows that the pH value of the bowel contents, which represent, in principle, a kind of aqueous solution or an aqueous medium, increases after passing the stomach, and that shortly before the reaching of the large intestine reaches a typical value of about 7. It is tried to use this increase to initiate the release of active ingredients. For this purpose active-ingredient containing cores are coated with anionic polymers which are dissolvable in aqueous solutions with a pH value above 7 (FIG. 1E). If the pH value rises above 7 shortly before the reaching of the large intestine, the coating dissolves and the formulation releases the active ingredients shortly before the entry into the large intestine. In order that the release takes place only in the large intestine, in some cases a slowly dissolving layer is applied underneath the enteric layer which delays the release for a short time, so that the release preferably does not already begin in the small intestine. Because the pH value maximally achieved in the small intestine is subject to an interindividual variability of clearly above one ph unit, a pH value of 7 is not exceeded with all individuals, so that in some cases it does not come to the intended release. If one lowers the threshold of solubility of the anionic polymer, for example, to Ph 6 in order to also achieve a release in these cases, thus with individuals with whom Ph 6 is exceeded shortly before the large intestine, the release takes place as intended, with individuals with whom pH 7 is exceeded shortly before the large intestine, the release, however, possibly takes place too early because with these individuals Ph 6 can already be exceeded in the jejunum. Such formulations which trigger the release depending on the exceedance of a certain pH value are depending on the pH value maximally achieved in the small intestine. They only function reliably, if in the target group of the individuals, with whom a release is intended in the large intestine the maximally achieved pH value, taking into account the interindividual variability, lies within certain margins. The area within these margins is also referred to as operating range in the further course. In order that it does not come to the non-appearance of the release, the threshold value of the anionic polymer must be lower or equal to the lower margin of the desired operating range of the formulation. However, a release can already occur when the pH value exceeds the lower margin of the operating range. Because the slope of the pH value from middle till the end of the small intestine is very low, and the threshold value of the anionic polymer should not already be exceeded in the middle of the small intestine, the operating range of such a technology is very narrow, typically about 0.5 ph units, which is not enough for most applications.
One knows that regardless of the interindividual variability of the intestinal pH value the pH value of the bowel contents falls by typically 1 to 1.5 units on passing the ileocecal valve, and it is tried to use this drop to initiate the release of active ingredients.
US20100209520 describes a three-layer system with which two layers control the release. A core free of active ingredient first is coated with an active-ingredient containing layer, there referred to as inner layer. Then the coated core is coated with a layer there referred to as intermediary layer made of a material which becomes dissolvable below a pH value of 6.6. Then a further coating takes place, referred to as outer layer, with a material which becomes dissolvable above a pH value of 7.0. The active ingredient is released if the pH value sinks below 6.6 upon the entry into the cecum, after it had previously risen above 7 after the exit from the stomach.
Because in certain embodiments the present invention has similar layers, but calls them differently, in the further course layers like the layer which is referred to as inner layer in US20100209520 are not called inner layers, but are considered as being components of active-ingredient containing cores. Layers similar to the intermediary layer are called most inner layers or “Caecal Coating” (FIG. 2, C), because these do not dissolve before the entry into the cecum. Layers similar to the outer layer of US20100209520 or similar to the layer made of the anionic polymers which are used for triggering of the release after exceedance of a certain pH value are called inner layers or “Enteric Coating” (FIG. 2, E). As outer or most outer layers only such layers are called which lie above an inner layer and preferably offer protection from humidity or neutral to basic saliva, in other words so-called “Protective Coatings” (FIG. 2, P).
The system disclosed in US20100209520 has the disadvantage that the pH value must at least rise above 7, and afterwards must at least drop below 6.6, in order that the release takes place.
Therefore the system is unsuitable if the pH value does not reliably exceed a value of 7 in the small intestine with the target group. With individuals with a lower maximal pH value in the small intestine no release takes place. It is as unsuitable if the pH value does not sink below 6.6 upon the entry into the small intestine. With individuals with a high maximal pH value in the small intestine and/or with individuals with a not very distinctive drop of the pH value upon the entry into the large intestine, also no release takes place. The range of pH values in which such a system can reliably release active ingredients in the large intestine (the operating range) is limited at the lower end by the threshold value of the inner layer, and at the upper end by the threshold value of the most inner layer, increased by the amount by which the pH value drops upon the entry into the large intestine. The reduction of the pH value upon the entry into the large intestine maximally necessary for the release is calculated as follows: Maximal value of the pH value in the small intestine to be expected with the target group less the threshold value below which the most inner layer becomes dissolvable. Because the height of the maximal pH value in the small intestine and the height of the drop of the pH value upon the entry into the large intestine are neither proportional, nor do they otherwise correlate, for a reliable release the reduction of the pH value maximally necessary for the release of a system must be lower, than the slightest drop of the pH value with the achievement of the large intestine occurring in the target group.
If the drop is not reliably higher than 1.4 pH units in the target group, the system disclosed in US20100209520 releases the active ingredient or ingredients reliably in the large intestine only in a range of the pH values maximally occurring in the small intestine from above 7 to below 8. If a maximal pH value in the small intestine of Ph 8.5 is reached with individuals of the target group, a drop of the pH value of over 1.9 pH units upon the achievement (reaching) of the large intestine can be necessary. The threshold value of the most inner layer, below which this becomes dissolvable or permeable (in the further course also called defined first pH value) is in addition not to be increased above the threshold value of the inner layer above which this becomes dissolvable or permeable (in the further course also called defined last pH value), because otherwise with very slow slope of the pH value the most inner coating would become dissolvable immediately after the inner coating without a drop of the pH value being necessary. Even an only slight increase of the threshold value of the most inner layer can lead to unintended release, because the pH value can have slight fluctuations in the course of the small intestine.
Also the threshold value of the inner layer may not be lowered below that of the most inner layer. It is not possible with this system to expand the limited operating range, to reduce the drop of the pH value upon the reaching of the large intestine maximally necessary for the release, or to increase the insensitiveness with respect to fluctuations of the pH value within the small intestine, without making worse at least one of both other parameters in each case. With a target group of individuals with which the slightest occurring drop of the pH value upon the reaching of the large intestine is not greater than the range, within which the individual maximal values of the pH value lie in the small intestine no reliable release in the large intestine can be achieved with this known technique. With this technique it is possible to reliably release active ingredients in the large intestine only if the drop of the pH value after passage of the ileocecal valve is larger than the interindividual variability of the maximal pH value in the small intestine. So the drop of the pH value within the digestive tract maximally necessary for the release is greater than the interindividual variability of the pH value maximally expected within the digestive tract before reaching of the ileocecal valve in the group of individuals, for which the substance or the substances are to be released, therefore greater than the necessary operating range. Operating range (AB), tolerance with respect to fluctuations of the pH value in the small intestine (ST) and necessary drop of the pH value upon the entry into the large intestine (EA) are tied together with systems in the state-of-the-art as follows:EA=AB+ST